Diabetes is a disease characterized by continued high blood glucose levels. The major conditions of diabetes are carbohydrate metabolism abnormality and lipid metabolism abnormality, and systemic complications of diabetes grow worse due to blood flow disturbance caused by high blood glucose levels and due to a decrease in sugar utilization. Such diabetic conditions are caused by the deficiency of hormone insulin, which regulates carbohydrate and lipid metabolisms, or insulin resistance.
Diabetes caused by the inability to secrete insulin is called “type 1 diabetes”, and diabetes caused by insulin resistance is called “type 2 diabetes”.
About 10% of the population in Korea was reported to be diabetic patients, and more than 90% of these patients are type 2 diabetic patients. In USA, there are nearly 20,000,000 diabetic patients, and about 95% of these diabetic patients are type 2 diabetic patients and are mainly obese people more than 45 years old. The incidence of type 2 diabetes is rapidly increasing worldwide, and the age of people suffering from type 2 diabetes also becomes young. Furthermore, Korea has the highest number of deaths caused by diabetes among OECD countries (March, 2007, Korean Medical Association).
Insulin is a hormone secreted by the β cells of the Langerhans islets in the pancreas. It regulates glucose metabolism and promotes the transport of glucose from the blood to the skeletal muscle, liver, adipose tissue, and other tissues, such that it can be utilized as an energy source or biosynthesized and stored as glycogen or fat.
Type 2 diabetes is a condition in which the body becomes resistant to insulin secreted from the pancreas, and the major function of insulin is impaired. It is a disease in which blood vessels are directly destroyed due to hyperinsulinemia, and metabolic syndrome becomes more severe. The mortality caused by diabetic complications is rapidly increasing worldwide.
Insulin resistance is a state in which insulin does not exhibit a function of transporting glucose into cells, due to the decrease of insulin receptor or due to the deficiency of receptor or signal transduction pathways through receptor. Such insulin resistance also appears obese persons or glucose-intolerant persons, who become diabetic. Such persons show an increase in blood glucose levels, even though insulin is normally secreted from the pancreas, and they become diabetic after several years, if the insulin resistance is not treated. The first stage of development of type 2 diabetes starts from insulin resistance in adipose tissue. In this stage, diabetes does not yet occur, but lipid metabolism abnormality appears due to insulin resistance. This stage is the disease condition of pre-diabetic obese persons or glucose-intolerant persons, the blood glucose levels of which increase to normal levels or higher, if they take glucose. Thus, though they are not diabetic, they can be prevented from the development of diabetes by treating insulin resistance. The present invention aims to invent a compound which can be used not only for the treatment of diabetes, but also for the prevention of development of diabetes.
The next stage is the stage of insulin resistance in not only adipose tissue, but also liver tissue or muscular tissue, which is the disease condition of type 2 diabetic patients. The compound of the present invention is a material that solves insulin resistance in adipose tissue, liver tissue and muscular tissue.
Many kinds of anti-diabetic drugs have been used to treat type 2 diabetes. However, drugs excluding biguanide metformin are primarily successful in lowering blood glucose levels, but do not show satisfactory effects on the prevention of important complications, including visual loss, heart failure, stroke, renal failure, peripheral neuropathy, foot ulcer, etc. Thus, through a guide for the use of anti-diabetic drugs (published in Diabete Care, August, 2006), the American Diabetes Association and the European Association for the Study of Diabetes commonly recommended to necessarily start treatment with metformin in type 2 diabetes. Also, the Korean Diabetes Association already started to recommend metformin as a primary drug (a report by the Research Institute for Healthcare Policy of Korean Medical Association, March, 2007).
Metformin is the only drug that has the same effect as that of insulin. However, it is an oral drug that does not cause a low blood glucose problem occurring in the case of insulin. Metformin is a drug that solves a problem of insulin resistance in adipose tissue, liver tissue and muscular cells. In addition, the blood glucose-lowering action and glycosylated hemoglobin level lowering action thereof are the most potent among all oral anti-diabetic drugs, and it has little or no side effects.
Sulfonylurea-based drugs, which have frequently been used to date, are drugs that lower blood glucose levels by enforcing insulin to be secreted from the pancreas. They accelerate the secretion of insulin in type 2 diabetic patients in which insulin secretion already decreased, and thus the degradation of secretory function of the pancreas is accelerated, such that the drug effect disappears and insulin injection is required. In addition, they can make lipid metabolism abnormal by promoting arteriosclerosis, increasing bodyweight and inducing low blood glucose levels, thus causing brain injuries.
Moreover, glitazone drugs appeared as drugs that solve the insulin resistance problem, but have no sufficient effect on blood glucose lowering, because they solve insulin resistance mainly in adipose tissue. For this reason, in most cases, they must be used in combination with metformin. A more important problem is that close attention is required in the use thereof, because mechanisms of side effects such as retinal vascular occlusion have been clearly found. Other oral anti-diabetic drugs are blood glucose lowering agents which are limited only to blood glucose lowering after a meal.
It can be seen in several papers that only metformin among oral anti-diabetic drugs is a drug of primary choice. Particularly, it was demonstrated that the effect of metformin activates AMPK, and thus the propriety of clinical effects thereof was demonstrated. AMPK is a key enzyme that physiologically regulates carbohydrate metabolism and lipid metabolism, and it was reported that metformin activates the enzyme, and thus has the effects of normalizing blood glucose levels, improving lipid conditions, normalizing irregular menstruation, ovulation and pregnancy, treating fatty liver, and preventing and treating cancers with deletion of P53 gene.
According to a report (Cancer research, July, 2007) by the Abramson Cancer Center of the University of Pennsylvania, metformin, an AMPK activator, is effective for the prevention and treatment of cancers with deletion of P53 gene. Accordingly, a compound of formula 1 according to the present invention, which has AMPK activity, can be effective for the prevention and treatment of cancer with deletion of P53 gene.
Metformin is administered three times a day, and the dosage thereof is more than 500 mg. Thus, to make sustained-release tablets which are administered once a day, tablets containing 1500-2250 mg of metformin must be prepared. These tablets are difficult to take, because they have a very large size. Accordingly, current sustained-release tablets, which are administered once at 24-hr intervals, are sold, containing only 750 mg of metformin per tablet.